Pharmaceutical manufacturing processes are typically carried out in carefully controlled environments. Conditions within those environments must be closely monitored. Those conditions include temperature as measured both within the product being processed and at selected locations within the controlled environment.
Freeze drying is a process that removes a solvent or suspension medium, typically water, from a product. Other solvents, such as alcohol, may also be removed in freeze drying processes.
In a freeze drying process for removing water, the water in the product is frozen to form ice and, under vacuum, the ice is sublimed and the vapor flows out of the product and towards a condenser. The water vapor is condensed on the condenser as ice and is later removed from the condenser. Freeze drying is particularly useful in the pharmaceutical and bio-pharmaceutical industries, as the integrity of the product is preserved during the freeze drying process and product stability can be guaranteed over relatively long periods of time. The present disclosure is also applicable to the food industry and other industries with similar requirements. The freeze dried product is ordinarily, but not necessarily, a biological substance.
Pharmaceutical freeze drying is often an aseptic process that requires sterile and carefully controlled conditions within a product drying chamber. It is critical to assure that all components of the freeze drying system coming into contact with the product are sterile.
Most freeze drying under aseptic conditions is done in a freeze dryer designed for vials, wherein product is contained in vials placed on trays or shelves. In one example of a prior art freeze drying system 100 shown in FIG. 1, a batch of product is placed in vials 112 arranged on freeze dryer trays 121 within a product drying chamber 110. Freeze dryer shelves 123 are used to support the trays 121 and to transfer heat to and from the trays and the product as required by the process. A heat transfer fluid flowing through conduits within the shelves 123 is used to remove or add heat. The product is initially cooled to freeze the solvent within the product, forming a frozen product.
The product drying chamber is then evacuated using a vacuum pump 150. Under vacuum, the frozen product in the vials 112 is heated slightly to cause sublimation of the ice within the product. Water vapor resulting from the sublimation of the ice flows through a passageway 115 into a condensing chamber 120 containing condensing coils or other surfaces 122 maintained below the condensation temperature of the water vapor. A coolant is passed through the coils 122 to remove heat, causing the water vapor to condense as ice on the coils.
Both the product drying chamber 110 and the condensing chamber 120 are maintained under vacuum during the process by the vacuum pump 150 connected to the exhaust of the condensing chamber 120. Non-condensable gases contained in the chambers 110, 120 are removed by the vacuum pump 150 and exhausted at a higher pressure outlet 152.
As the freeze drying process progresses, a sublimation front forms in each vial and moves from the exposed top surface of the product to the bottom of the vial. The sublimation front defines a boundary between freeze dried product above the front, and frozen product containing frozen solvent below the front. In an individual vial, the freeze drying process is complete when the sublimation front reaches the bottom of the vial.
Accurately and non-invasively monitoring product attributes such as temperature during and after the process with minimal bias from the monitoring sensor is critical to process development and to work related to process scale-up, especially in the pharma/bio-pharmaceutical industry. For example, the ability to control product temperature below a critical value is essential for a successful batch of freeze-dried product. However, introducing a monitoring probe into the product contained in a processing vial may bias characteristics of the product in that vial, making the vial atypical of the rest of the batch. Specifically, the physical presence of self-supporting thermocouple probes in the measured vials alters the thermal conditions in those vials. For example, self-supporting probes containing bimetal thermocouples have a different thermal conductivity and a different heat capacity from the surrounding frozen product. The thermal characteristics of a probe furthermore remain constant, while those of the surrounding product change as frozen solvent in the product sublimes. Measurements from those probes are therefore approximations of the thermal conditions in neighboring vials that do not contain probes.
In existing systems, the product temperature is typically monitored by using wired thermocouple probes that are connected to electrical ports provided in the product drying chamber for that purpose. Because of the variation in heat transfer among the multiple shelves on which the product vials are placed, the product attributes, including temperature, are position-dependent within the product drying chamber. To monitor temperature in an existing system, multiple (typically 8-16) single-point self-supporting probes are placed in separate, selected vials in a development cycle to understand that positional variation. Such a setup, with multiple sensor wires across the vials placed in the product chamber, can be cumbersome to handle and can sometimes lead to product loss and/or errors in data collection.
Wireless, induction-based sensors that wirelessly communicate with a data acquisition system are also used. The induction-based probes have a typical sensing junction size of approximately 1.5 cm×0.5 cm.
There is a need for an improved technique for monitoring product conditions both during the development of a freeze drying process and during production. The technique should be non-invasive, permitting measurements of product conditions without changing those conditions, and should utilize inexpensive, easily fabricated sensors. The technique should furthermore eliminate the potential errors and process disruption caused by wired probes. The technique should maximize measurement resolution within the volume of the product drying chamber and within the vial. The technique should provide real time data that may be used in controlling the freeze drying process.